FM381 is a potent covalent reversible inhibitor of JAK3 targeting the unique Cys909 at the gatekeeper position +7 in JAK3. FM-381 has an IC50 of 127 pM for JAK3, with 410, 2700 and 3600-fold selectivity over JAK1, JAK2 and TYK2, respectively.
JAK3 (Janus Kinase 3) is a non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. JAK3 mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, JAK3 plays a pivotal role in signal transduction. Following ligand binding to cell surface receptors, JAK3 phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, JAK3 phosphorylates the STATs proteins once they are recruited to the receptor.
FM-381 is a JAK3 selective inhibitor with IC50 of 127pM, while its IC50s against JAK1, JAK2 and TYK2 were 52nM, 346nM and 459nM, respectively[1]. Using an in cell NanoBRET assay system, the EC50 of FM-381 on JAK3 inhibitory was 237nM, while no effect was detected on JAK1, JAK2 or BTK kinase at the concentration of 10000nM[2]. In a STAT phosphorylation assay utilizing primary human T-cells, FM-381 showed significant inhibition of IL-2 induced STAT5 phosphorylation at concentrations around 50 to 100nM, reduced IL-4 induced STAT6 phosphorylation at concentrations around 300nM. The JAK3-independent IL-6 induced STAT3 or IFN-α induced STAT1 phosphorylation were not influenced by FM-381 at the concentration up to 1000nM, thus further confirming the selectivity of FM-381 for JAK3[2].
作用机制
Covalent bond formation that could be reversed under physiological conditions were detected between FM-381 and the C909 residue in JAK3 kinase by X-ray structural studies[2].
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